Electrical Stimulation Treatment of Bronchial Constriction

ABSTRACT

Methods and devices for treating bronchial constriction related to asthma and anaphylaxis wherein the treatment includes providing an electrical impulse to a selected region of the vagus nerve and/or the lungs of a patient suffering from bronchial constriction.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of co-pending U.S. patent applicationSer. No. 11/591,340 filed Nov. 1, 2006 which claims the benefit of U.S.Provisional Patent Application Nos: 60/736,001, filed Nov. 10, 2005;60/772,361, filed Feb. 10, 2006; 60/814,313, filed Jun. 16, 2006; and60/786,564, filed Mar. 28, 2006, the entire disclosures of which arehereby incorporated by reference and also claims the benefit of U.S.Provisional Patent Application No. 60/736,002, filed Nov. 10, 2005.

BACKGROUND OF THE INVENTION

The present invention relates to the field of delivery of electricalimpulses (and/or fields) to bodily tissues for therapeutic purposes, andmore specifically to devices and methods for treating conditionsassociated with bronchial constriction

There are a number of treatments for various infirmities that requirethe destruction of otherwise healthy tissue in order to affect abeneficial effect. Malfunctioning tissue is identified, and thenlesioned or otherwise compromised in order to affect a beneficialoutcome, rather than attempting to repair the tissue to its normalfunctionality. While there are a variety of different techniques andmechanisms that have been designed to focus lesioning directly onto thetarget nerve tissue, collateral damage is inevitable.

Still other treatments for malfunctioning tissue can be medicinal innature, in many cases leaving patients to become dependent uponartificially synthesized chemicals. Examples of this are anti-asthmadrugs such as albuterol, proton pump inhibitors such as omeprazole(Prilosec), spastic bladder relievers such as Ditropan, and cholesterolreducing drugs like Lipitor and Zocor. In many cases, these medicinalapproaches have side effects that are either unknown or quitesignificant, for example, at least one popular diet pill of the late1990's was subsequently found to cause heart attacks and strokes.

Unfortunately, the beneficial outcomes of surgery and medicines are,therefore, often realized at the cost of function of other tissues, orrisks of side effects.

The use of electrical stimulation for treatment of medical conditionshas been well known in the art for nearly two thousand years. It hasbeen recognized that electrical stimulation of the brain and/or theperipheral nervous system and/or direct stimulation of themalfunctioning tissue, which stimulation is generally a whollyreversible and non-destructive treatment, holds significant promise forthe treatment of many ailments.

Electrical stimulation of the brain with implanted electrodes has beenapproved for use in the treatment of various conditions, including painand movement disorders including essential tremor and Parkinson'sdisease. The principle behind these approaches involves disruption andmodulation of hyperactive neuronal circuit transmission at specificsites in the brain. As compared with the very dangerous lesioningprocedures in which the portions of the brain that are behavingpathologically are physically destroyed, electrical stimulation isachieved by implanting electrodes at these sites to, first senseaberrant electrical signals and then to send electrical pulses tolocally disrupt the pathological neuronal transmission, driving it backinto the normal range of activity. These electrical stimulationprocedures, while invasive, are generally conducted with the patientconscious and a participant in the surgery.

Brain stimulation, and deep brain stimulation in particular, is notwithout some drawbacks. The procedure requires penetrating the skull,and inserting an electrode into the brain matter using a catheter-shapedlead, or the like. While monitoring the patient's condition (such astremor activity, etc.), the position of the electrode is adjusted toachieve significant therapeutic potential. Next, adjustments are made tothe electrical stimulus signals, such as frequency, periodicity,voltage, current, etc., again to achieve therapeutic results. Theelectrode is then permanently implanted and wires are directed from theelectrode to the site of a surgically implanted pacemaker. The pacemakerprovides the electrical stimulus signals to the electrode to maintainthe therapeutic effect. While the therapeutic results of deep brainstimulation are promising, there are significant complications thatarise from the implantation procedure, including stroke induced bydamage to surrounding tissues and the neurovasculature.

One of the most successful modern applications of this basicunderstanding of the relationship between muscle and nerves is thecardiac pacemaker. Although its roots extend back into the 1800's, itwas not until 1950 that the first practical, albeit external and bulkypacemaker was developed. Dr. Rune Elqvist developed the first trulyfunctional, wearable pacemaker in 1957. Shortly thereafter, in 1960, thefirst fully implanted pacemaker was developed.

Around this time, it was also found that the electrical leads could beconnected to the heart through veins, which eliminated the need to openthe chest cavity and attach the lead to the heart wall. In 1975 theintroduction of the lithium-iodide battery prolonged the battery life ofa pacemaker from a few months to more than a decade. The modernpacemaker can treat a variety of different signaling pathologies in thecardiac muscle, and can serve as a defibrillator as well (see U.S. Pat.No. 6,738,667 to Deno, et al., the disclosure of which is incorporatedherein by reference).

Another application of electrical stimulation of nerves has been thetreatment of radiating pain in the lower extremities by means ofstimulation of the sacral nerve roots at the bottom of the spinal cord(see U.S. Pat. No. 6,871,099 to Whitehurst, et al., the disclosure ofwhich is incorporated herein by reference).

The smooth muscles that line the bronchial passages are controlled by aconfluence of vagus and sympathetic nerve fiber plexuses. Spasms of thebronchi during asthma attacks and anaphylactic shock can often bedirectly related to pathological signaling within these plexuses.Anaphylactic shock and asthma are major health concerns.

Asthma, and other airway occluding disorders resulting from inflammatoryresponses and inflammation-mediated bronchoconstriction, affects anestimated eight to thirteen million adults and children in the UnitedStates. A significant subclass of asthmatics suffers from severe asthma.An estimated 5,000 persons die every year in the United States as aresult of asthma attacks. Up to twenty percent of the populations ofsome countries are affected by asthma, estimated at more than a hundredmillion people worldwide. Asthma's associated morbidity and mortalityare rising in most countries despite increasing use of anti-asthmadrugs.

Asthma is characterized as a chronic inflammatory condition of theairways. Typical symptoms are coughing, wheezing, tightness of the chestand shortness of breath. Asthma is a result of increased sensitivity toforeign bodies such as pollen, dust mites and cigarette smoke. The body,in effect, overreacts to the presence of these foreign bodies in theairways. As part of the asthmatic reaction, an increase in mucousproduction is often triggered, exacerbating airway restriction. Smoothmuscle surrounding the airways goes into spasm, resulting inconstriction of airways. The airways also become inflamed. Over time,this inflammation can lead to scarring of the airways and a furtherreduction in airflow. This inflammation leads to the airways becomingmore irritable, which may cause an increase in coughing and increasedsusceptibility to asthma episodes.

Two medicinal strategies exist for treating this problem for patientswith asthma. The condition is typically managed by means of inhaledmedications that are taken after the onset of symptoms, or by injectedand/or oral medication that are taken chronically. The medicationstypically fall into two categories; those that treat the inflammation,and those that treat the smooth muscle constriction. The first is toprovide anti-inflammatory medications, like steroids, to treat theairway tissue, reducing its tendency to over-release of the moleculesthat mediate the inflammatory process. The second strategy is to providea smooth muscle relaxant (an anti-cholinergic and/or anti-adrenergicmedication) to reduce the ability of the muscles to constrict.

It has been highly preferred that patients rely on avoidance of triggersand anti-inflammatory medications, rather than on the bronchodilators astheir first line of treatment. For some patients, however, thesemedications, and even the bronchodilators are insufficient to stop theconstriction of their bronchial passages, and more than five thousandpeople suffocate and die every year as a result of asthma attacks.

Anaphylaxis likely ranks among the other airway occluding disorders ofthis type as the most deadly, claiming more than eight thousand deathsper year in the United States alone. Anaphylaxis (the most severe fromof which is anaphylactic shock) is a severe and rapid systemic allergicreaction to an allergan. Minute amounts of allergans may cause alife-threatening anaphylactic reaction. Anaphylaxis may occur afteringestion, inhalation, skin contact or injection of an allergan.Anaphylactic shock usually results in death in minutes if untreated.Anaphylactic shock is a life-threatening medical emergency because ofrapid constriction of the airway. Brain damage sets in quickly withoutoxygen. Anaphylactic shock itself accounts for approximately 1,500deaths every year in the United States.

The triggers for these fatal reactions range from foods (nuts andshellfish), to insect stings (bees), to medication (radiocontrasts andantibiotics). It is estimated 1.3 to 13 million people in the UnitedStates are allergic to venom associated with insect bites; 27 millionare allergic to antibiotics; and 5-8 million suffer food allergies. Allof these individuals are at risk of anaphylactic shock from exposure toany of the foregoing allergens. In addition, anaphylactic shock can bebrought on by exercise. Yet all are mediated by a series ofhypersensitivity responses that result in uncontrollable airwayocclusion driven by smooth muscle constriction, and dramatic hypotensionthat leads to shock. Cardiovascular failure, multiple organ ischemia,and asphyxiation are the most dangerous consequences of anaphylaxis.

Anaphylactic shock requires advanced medical care immediately. Currentemergency measures include rescue breathing; administration ofepinephrine; and/or intubation if possible. Rescue breathing may behindered by the closing airway but can help if the victim stopsbreathing on his own. Clinical treatment typically consists ofantihistamines (which inhibit the effects of histamine at histaminereceptors) which are usually not sufficient in anaphylaxis, and highdoses of intravenous corticosteroids. Hypotension is treated withintravenous fluids and sometimes vasoconstrictor drugs. Forbronchospasm, bronchodilator drugs such as salbutamol are employed.

Given the common mediators of both asthmatic and anaphylacticbronchoconstriction, it is not surprising that asthma sufferers are at aparticular risk for anaphylaxis. Still, estimates place the numbers ofpeople who are susceptible to such responses at more than 40 million inthe United States alone.

Tragically, many of these patients are fully aware of the severity oftheir condition, and die while struggling in vain to manage the attackmedically. Many of these incidents occur in hospitals or in ambulances,in the presence of highly trained medical personnel who are powerless tobreak the cycle of inflammation and bronchoconstriction (andlife-threatening hypotension in the case of anaphylaxis) affecting theirpatient.

Unfortunately, prompt medical attention for anaphylactic shock andasthma are not always available. For example, epinephrine is not alwaysavailable for immediate injection. Even in cases where medication andattention is available, life saving measures are often frustratedbecause of the nature of the symptoms. Constriction of the airwaysfrustrates resuscitation efforts, and intubation may be impossiblebecause of swelling of tissues.

Typically, the severity and rapid onset of anaphylactic reactions doesnot render the pathology amenable to chronic treatment, but requiresmore immediately acting medications. Among the most popular medicationsfor treating anaphylaxis is epinephrine, commonly marketed in so-called“Epi-pen” formulations and administering devices, which potentialsufferers carry with them at all times. In addition to serving as anextreme bronchodilator, epinephrine raises the patient's heart ratedramatically in order to offset the hypotension that accompanies manyreactions. This cardiovascular stress can result in tachycardia, heartattacks and strokes.

Unlike cardiac arrhythmias, which can be treated chronically withpacemaker technology, or in emergent situations with equipment likedefibrillators (implantable and external), there is virtually nocommercially available medical equipment that can chronically reduce thebaseline sensitivity of the muscle tissue in the airways to reduce thepredisposition to asthma attacks, or to break the cycle of bronchialconstriction associated with an acute asthma attack or anaphylaxis.

Accordingly, there is a need in the art for new products and methods fortreating the immediate symptoms of anaphylactic shock and asthma.

SUMMARY OF THE INVENTION

The present invention involves products and methods of treatment ofasthma, anaphylaxis, and other pathologies involving the constriction ofthe primary airways, utilizing an electrical signal that may be appliedto the vagus nerve to temporarily block and/or modulate the signals inthe vagus nerve.

In a first embodiment, the present invention contemplates an electricalimpulse delivery device that delivers one or more electrical impulses toat least one selected region of the vagus nerve to block and/or modulatesignals to the muscle fibers surrounding the bronchi, and/or blockand/or affect histamine response of the vagus nerve, facilitatingopening of airways.

In another embodiment, methods in accordance with the present inventioncontemplate delivery of one or more electrical impulses to at least oneselected region of the vagus nerve to block and/or modulate signals tothe muscle fibers surrounding the bronchi, and/or block and/or affecthistamine response of the vagus nerve, facilitating opening of airways.

It shall be understood that the activation of such impulses may bedirected manually by a patient suffering from bronchospasm, depending onthe embodiment.

In one or more embodiments, the impulses are applied in a manner thatblocks and/or affects the constriction of the smooth muscle lining thebronchial passages to relieve the spasms that occur during anaphylacticshock or asthma attacks. The impulses may be applied by positioningleads on the nerves that control bronchial activity such as the anteriorand posterior bronchial branches of the right and left branches of thevagus nerve, which join with fibers from the sympathetic nerve chain toform the anterior and posterior pulmonary plexuses. Leads may bepositioned above both the pulmonary and cardiac branches of the vagusnerve to include a stimulus and/or blocking and/or modulation of bothorgans. It shall also be understood that leadless impulses as shown inthe art may also be utilized for applying impulses to the targetregions.

The mechanisms by which the appropriate impulse is applied to theselected region of the vagus nerve can include positioning the distalends of an electrical lead or leads in the vicinity of the nervoustissue controlling the pulmonary and/or cardiac muscles, which leads arecoupled to an implantable or external electrical impulse generatingdevice. The electric field generated at the distal tip of the leadcreates a field of effect that permeates the target nerve fibers andcauses the blocking and/or modulation of signals to the subject muscles,and/or the blocking and/or affecting of histamine response.

The application of electrical impulses, either to the vagus nerve or thefibers branching off the vagus nerve to the bronchial muscles tomodulate the parasympathetic tone in order to relax the smooth muscle orblock and/or affect the constriction of the bronchial passageways toreduce airway constriction during pathological inflammatory responsesthat are associated with asthma and anaphylaxis, is more completelydescribed in the following detailed description of the invention, withreference to the drawings provided herewith, and in claims appendedhereto.

The inventors submit that the cause of many physiological disorders maybe a dysfunction in any one nerve, or a combination of nerves and/ornerve clusters (ganglia and/or plexuses), and that the proper treatmentof such a dysfunction by electrical stimulation cannot be effectivewithout a method that takes these alternative pathologies intoconsideration. More particularly, with respect to organ function,including but not limited to the respiratory, cardiovascular, digestive,reproductive, and renal-urinary systems, the nerves most directlyinvolved with motor and sensory control are those of the tenth cranialnerve (the vagus nerve) and the sympathetic nerves. It shall beunderstood that the sympathetic nerve fibers emanating from the chainthat extends along the anterior outside of the vertebral column, inconjunction with the fibers of the spinal cord nerve roots that joinwith the sympathetic fibers, form the sympathetic nervous system. Theplexuses and ganglia, such as the celiac, pulmonary, cardiac, hepatic,mesenteric plexuses, that control the organ function are formed, fromone side by, the afferent and efferent fibers of the vagus nerve (or inlimited instances by others of the cranial nerves) and on the other sideby the fibers of the sympathetic nervous system. The present inventionhas applicability in treating disorders that benefit from simultaneousmonitoring and/or modulation of one or more sympathetic nerves, or oneor more cranial nerves, or the plexus formed by the interaction of thetwo.

Specifically, the treatment regiments contemplated by the inventors ofthe present invention include the holistic monitoring of at least two of(i) the sympathetic nerve fibers (at a location distal to thesympathetic chain such that the spinal cord nerve root fibers areincorporated into the fiber bundle), (ii) the fibers of the cranialnerve branch responsible for communication with the organ or targettissue, (iii) the plexus wherein these two nerve fibers communicate,(iv) the muscles surrounding or interfacing with the pathologicallyresponding tissue, and (v) any physical state of being that may beassociated with the condition, and thusly creating a stimulation signalpattern based upon the evaluation of the monitoring such that thedesired therapeutic effect results.

More specifically, the inventors hereof have made the realization thatthe control of the organ and/or tissue is the result of a circuit thatbegins in the brain, and may include at least three separate descendingcomponents, i.e., the cranial nerve, the sympathetic nerve fibers, andthe spinal cord nerve roots. This circuit is, in fact, an electricalcircuit, and most importantly it is being disclosed herein that it ismost effective, when attempting to modify the behavior of a component inan electrical circuit, to determine the nature and function of as manyof (and preferably all of) the components of the circuit before simplydriving a signal into the system. This requires monitoring theappropriate components and accurately analyzing the results of thatmonitoring.

Physiological disorders that may be treated by this monitoring of theentire circuit, and then applying the corrective signal to theappropriate component of the system, include, but are not limited tointestinal motility disorders, sexual dysfunction, bronchial disorder(such as asthma), dysfunction of the liver, pancreatic disorders, andheart disorders, pulmonary disorders, gastrointestinal disorders, andrenal and urinary complaints. The number of disorders to be treated islimited only by the number, variety, and placement of electrodes (orcombinations of multiple electrodes) along the sympathetic nervoussystem and cranial nervous system.

In general, an allergic response is an increasing cause of adult-onsetasthma cases. The allergic process, called atopy, and its connection toasthma, involves various airborne allergens or other triggers that setoff a cascade of events in the immune system leading to inflammation andhyperreactivity in the airways. One description of the allergic processis as follows: The primary contributor to allergies and asthma appearsto be a category of white blood cells known as helper T-cells, inparticular a subgroup called TH2-cells. TH2-cells overproduceinterleukins (Ls), immune factors that are molecular members of a familycalled cytokines, powerful agents of the inflammatory process.

Interleukins 4, 9, and 13, for example, may be responsible for afirst-phase asthma attack. These interleukins stimulate the productionand release of antibody groups known as immunoglobulin E (IgE). Peoplewith both asthma and allergies appear to have a genetic predispositionfor overproducing IgE. During an allergic attack, these IgE antibodiescan bind to special cells in the immune system called mast cells, whichare generally concentrated in the lungs, skin, and mucous membranes.This bond triggers the release of a number of active chemicals,importantly potent molecules known as leukotrienes. These chemicalscause airway spasms, overproduce mucus, and activate nerve endings inthe airway lining.

Another cytokine, interleukin 5, appears to contribute to a late-phaseinflammatory response. This interleukin attracts white blood cells knownas eosinophils. These cells accumulate and remain in the airways afterthe first attack. They persist for weeks and mediate the release ofother damaging particles that remain in the airways.

Over the course of years the repetition of the inflammatory eventsinvolved in asthma can cause irreversible structural and functionalchanges in the airways, a process called remodeling. The remodeledairways are persistently narrow and can cause chronic asthma.

In accordance with one or more embodiments of the present invention, amethod of treating bronchial constriction includes inducing at least oneof an electric field and electromagnetic field in one or more lungs of amammal such that one or more mitogenic factors, and that contribute tobronchial constriction are down-regulated. The mitogenic factor mayinclude vascular endothelial growth factor (VEGF). Additionally oralternatively, the mitogenic factor may effect the production ofT-helper type 2 cells (TH2).

Additionally or alternatively, the mitogenic factor may include one ormore enzymes, such as one or more matrix metalloproteinases (MMPs). Theone or more MMPs may include one or more of: Stromelysin-1, gelatinaseA, fibroblast collagenase (MMP-1), neutrophil collagenase (MMP-8),gelatinase B (MMP-9), stromelysin-2 (MMP-10), stromelysin-3 (MMP-11),matrilysin (MMP-7), collagenase 3 (MMP-13), and TNF-alpha convertingenzyme (TACE).

One or more embodiments may include inducing the field(s) by applying atleast one electrical impulse to one or more field emitters. The one ormore field emitters may be disposed percutaneously and/or subcutaneouslyto direct the field(s) toward the lung(s). For example, the one or morefield emitters may be disposed at least one of on a chest of the mammaland on the back of the mammal. The one or more field emitters mayinclude at least one of capacitive coupling electrodes and inductivecoils.

One or more embodiments may include applying drive signals to the one ormore field emitters to produce the at least one impulse and induce thefield(s). The drive signals may include at least one of sine waves,square waves, triangle waves, exponential waves, and complex impulses.For example, the drive signals include a frequency of between about 10Hz to 100 KHz, a duty cycle of between about 1 to 100%, and/or anamplitude of between about 1 mv/cm to about 50 mv/cm. The field(s) maybe applied for a predetermined period of time, for example, betweenabout 0.5 to about 24 hours.

Preferably, a response of the mammal to the field(s) is measured (e.g.,airway pressure and/or lung volume), such that data collection and/orfield adjustments may be made.

Ultimately, the inventors hereof recognize that the treatment ofdisorders having common symptoms may have entirely different causes, andas such must be distinguished from one another if an effective treatmentis to be developed. Nowhere is this principle truer than in thepotential treatment of ailments through stimulation of the nerves thatcontrol the peripheral organs and/or tissues.

Other aspects, features, advantages, etc. will become apparent to oneskilled in the art when the description of the invention herein is takenin conjunction with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

For the purposes of illustrating the various aspects of the invention,there are shown in the drawings forms that are presently preferred, itbeing understood, however, that the invention is not limited by or tothe precise data, methodologies, arrangements and instrumentalitiesshown, but rather only by the claims.

FIG. 1 is a diagrammatic view of the sympathetic and parasympatheticnerve systems;

FIG. 2 is a cross-sectional anatomical illustration of selected portionsof a neck, thoracic and abdominal region;

FIG. 3 illustrates a simplified view of the vagus nerve shown in FIGS. 1and 2;

FIG. 4 illustrates an exemplary electrical voltage/current profile for ablocking and/or modulating impulse applied to a portion or portions ofthe vagus nerve in accordance with an embodiment of the presentinvention;

FIGS. 5-14 graphically illustrate exemplary experimental data obtainedin accordance with multiple embodiments of the present invention;

FIGS. 15-20 graphically illustrate the inability of signals taught byU.S. patent application Ser. No. 10/990,938 to achieve the results ofthe present invention;

FIG. 21 is a schematic diagram of the human autonomic nervous system,illustrating sympathetic fibers, spinal nerve root fibers, and cranialnerves;

FIG. 22 is a further schematic diagram of the human autonomic nervoussystem and a modulation system therefore in accordance with one or moreembodiments of the present invention; and

FIG. 23 is a process flow diagram illustrating process steps that may becarried out for the treatment of disorders using neuromuscularmodulation in accordance with one or more embodiments of the presentinvention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

It shall be understood that the embodiments disclosed herein arerepresentative of preferred aspects of the invention and are so providedas examples of the invention. The scope of the invention, however, shallnot be limited to the disclosures provided herein, nor by theprovisional claims appended hereto.

Treatment Approach 1

While the exact physiological causes of asthma and anaphylaxis have notbeen determined, the present invention postulates that the directmediation of the smooth muscle constriction is the result ofover-activity in the vagus nerve, which is a response to the flood ofpro-inflammatory mediators' interacting with the receptors on the nervefibers themselves.

It has been observed in the literature that the nervous system maintainsa balance of the signals carried by the sympathetic and parasympatheticnerves. The vagus nerve, as the source of the signal to constrictbronchial smooth muscle, is thought to provide a baseline level oftonicity in the smooth muscles surrounding the bronchial passages, inorder to prevent the tissue lining the airways from collapsing shut.

Specifically, one or more embodiments of the present invention considerthe signals carried by the vagus (parasympathetic) nerve to cause aconstriction of the smooth muscle surrounding the bronchial passages.The sympathetic nerve fibers carry the opposing signals that tend toopen the bronchial passages. It should be recognized that the signals ofthe vagus nerve mediate a response similar to that of histamine, whilethe sympathetic signals generate an effect similar to epinephrine. Giventhe postulated balance between the parasympathetic and sympatheticsignals, removing the parasympathetic signal should create an imbalanceemphasizing the sympathetic signal. Along these lines, scientificliterature also indicates that severing the vagus nerve in dogs willopen the bronchial passages, much the same way that epinephrine does.

Now referring to FIGS. 1 and 2, the vagus nerve is shown in more detail.The vagus nerve is composed of motor and sensory fibers. The vagus nerveleaves the cranium and is contained in the same sheath of dura matterwith the accessory nerve. The vagus nerve passes down the neck withinthe carotid sheath to the root of the neck. The branches of distributionof the vagus nerve include, among others, the superior cardiac, theinferior cardiac, the anterior bronchial and the posterior bronchialbranches. On the right side, the vagus nerve descends by the trachea tothe back of the root of the lung, where it spreads out in the posteriorpulmonary plexus. On the left side, the vagus nerve enters the thorax,crosses the left side of the arch of the aorta, and descends behind theroot of the left lung, forming the posterior pulmonary plexus.

In mammals, two vagal components have evolved in the brainstem toregulate peripheral parasympathetic functions. The dorsal vagal complex(DVC), consisting of the dorsal motor nucleus (DMNX) and itsconnections, controls parasympathetic function below the level of thediaphragm, while the ventral vagal complex (VVC), comprised of nucleusambiguus and nucleus retrofacial, controls functions above the diaphragmin organs such as the heart, thymus and lungs, as well as other glandsand tissues of the neck and upper chest, and specialized muscles such asthose of the esophageal complex.

The parasympathetic portion of the vagus innervates ganglionic neuronswhich are located in or adjacent to each target organ. The VVC appearsonly in mammals and is associated with positive as well as negativeregulation of heart rate, bronchial constriction, vocalization andcontraction of the facial muscles in relation to emotional states.Generally speaking, this portion of the vagus nerve regulatesparasympathetic tone. The VVC inhibition is released (turned off) instates of alertness. This in turn causes cardiac vagal tone to decreaseand airways to open, to support responses to environmental challenges.

The parasympathetic tone is balanced in part by sympathetic innervation,which generally speaking supplies signals tending to relax the bronchialmuscles so overconstriction does not occur.

Overall, airway smooth muscle tone is dependent on several factors,including parasympathetic input, inhibitory influence of circulatingepinephrine, NANC inhibitory nerves and sympathetic innervation of theparasympathetic ganglia. Stimulation of the vagus nerve (upregulation oftone), such as occurs in asthma attacks or anaphylactic shock, resultsin airway constriction and a decrease in heart rate. In general, thepathology of both severe asthma and anaphylaxis appear to be mediated byinflammatory cytokines that overwhelm receptors on the nerve cells andcause the cells to massively upregulate the parasympathetic tone.

In the case of asthma, it appears that the airway tissue has both (i) ahypersensitivity to the allergen that causes the overproduction of thecytokines that stimulate the cholenergic receptors of the nerves and/or(ii) a baseline high parasympathetic tone or a high ramp up to a strongparasympathetic tone when confronted with any level of cholenergiccytokine. The combination can be lethal. Anaphylaxis appears to bemediated predominantly by the hypersensitivity to an allergen causingthe massive overproduction of cholenergic receptor activating cytokinesthat overdrive the otherwise normally operating vagus nerve to signalmassive constriction of the airways. Drugs such as epinephrine driveheart rate up while also relaxing the bronchial muscles, effectingtemporary relief of symptoms from these conditions. As mentioned above,experience has shown that severing the vagus nerve (an extreme versionof reducing the parasympathetic tone) has an effect similar to that ofepinephrine and adrenaline on heart rate and bronchial diameter in thatthe heart begins to race (tachycardia) and the bronchial passagewaysdilate.

In accordance with at least one aspect of the present invention, thedelivery, in a patient suffering from severe asthma or anaphylacticshock, of an electrical impulse sufficient to block and/or modulatetransmission of signals will result in relaxation of the bronchi smoothmuscle, dilating airways and/or counteract the effect of histamine onthe vagus nerve. Depending on the placement of the impulse, the signalblocking and/or modulation can also raise the heart function.

In accordance with at least one aspect of the present invention,blocking and/or modulating the signal in the vagus nerve, and/orblocking and/or affecting the histamine response of the vagus nerve, toreduce parasympathetic tone provides an immediate emergency response,much like a defibrillator, in situations of severe asthma attacks oranaphylactic shock, providing immediate temporary dilation of theairways and optionally an increase of heart function until subsequentmeasures, such as administration of epinephrine, rescue breathing andintubation can be employed.

Moreover, the teachings of the present invention permit immediate airwaydilation and/or heart function increase to enable subsequent life savingmeasures that otherwise would be ineffective or impossible due to severeconstriction or other physiological effects. Treatment in accordancewith the present invention provides bronchodilation and optionallyincreased heart function for a long enough period of time so thatadministered medication such as epinephrine has time to take effectbefore the patient suffocates.

The methods described herein of applying an electrical impulse to aselected region of the vagus nerve may further be refined such that theat least one region may comprise at least one nerve fiber emanating fromthe patient's tenth cranial nerve (the vagus nerve), and in particular,at least one of the anterior bronchial branches thereof, oralternatively at least one of the posterior bronchial branches thereof.Preferably the impulse is provided to at least one of the anteriorpulmonary or posterior pulmonary plexuses aligned along the exterior ofthe lung. As necessary, the impulse may be directed to nervesinnervating only the bronchial tree and lung tissue itself. In addition,the impulse may be directed to a region of the vagus nerve to blockand/or modulate both the cardiac and bronchial branches. As recognizedby those having skill in the art, this embodiment should be carefullyevaluated prior to use in patients known to have preexisting cardiacissues.

Further reference is now made to FIG. 3, which illustrates a simplifiedview of the vagus nerve shown in FIG. 2 and cardiac and pulmonarybranches thereof. Also shown is a vagus nerve stimulation (VNS) device300 for stimulation of the vagus nerve. VNS device 300 is intended forthe treatment of bronchial constriction or hypotension associated withanaphylactic shock or asthma. VNS device 300 may include an electricalimpulse generator 310; a power source 320 coupled to the electricalimpulse generator 310; a control unit 330 in communication with theelectrical impulse generator 310 and coupled to the power source 320;and electrodes 340 coupled to the electrical impulse generator 310 forattachment via leads 350 to one or more selected regions 200A, 200B of avagus nerve 200 of a mammal. The control unit 330 may control theelectrical impulse generator 310 for generation of a signal suitable foramelioration of the bronchial constriction or hypotension when thesignal is applied via the electrodes 340 to the vagus nerve 200. It isnoted that VNS device 300 may be referred to by its function as a pulsegenerator.

In accordance with one embodiment, one or more electrical impulses aredirected to location A on or near the vagus nerve above the cardiacbranch. In this embodiment one or more electrical impulses areintroduced at the location A to block and/or modulate and/or inhibitupregulation of the parasympathetic tone and effect a dilation ofairways and increase in heart function.

In accordance with another embodiment, one or more electrical impulsesare directed to location B on or near the vagus nerve below the cardiacbranch proximal to the pulmonary branch. In this embodiment one or moreelectrical impulses are introduced at the location B to block and/ormodulate and/or inhibit upregulation of the parasympathetic tone toeffect only a dilation of airways.

In patients known to be subject to anaphylactic shock or severe asthmaattacks, one or more electrical impulse emitting devices 300 may beimplanted in one or more selected regions 200A, 200B of the vagus nerve200. Device 300 may be percutaneous for emergency applications, whereindevice 300 may comprise an electrode 340 powered via an external powersource 320.

U.S. Patent Application Publications 2005/0075701 and 2005/0075702, bothto Shafer, both of which are incorporated herein by reference, relatingto stimulation of neurons of the sympathetic nervous system to attenuatean immune response, contain descriptions of pulse generators that may beapplicable to the present invention.

FIG. 4 illustrates an exemplary electrical voltage/current profile for ablocking and/or modulating impulse applied to a portion or portions ofthe vagus nerve in accordance with an embodiment of the presentinvention.

With reference to FIG. 4, a suitable electrical voltage/current profile400 for the blocking and/or modulating impulse 410 to the portion orportions 200A, 200B of the vagus nerve 200 may be achieved using a pulsegenerator 310. In a preferred embodiment, the pulse generator 310 may beimplemented using a power source 320 and a control unit 330 having, forinstance, a processor, a clock, a memory, etc., to produce a pulse train420 to the electrode(s) 340 that deliver the blocking and/or modulatingimpulse 410 to the nerve 200 via leads 350. For percutaneous use, theVNS device 300 may be available to the surgeon as external emergencyequipment. For subcutaneous use, the VNS device 300 may be surgicallyimplanted, such as in a subcutaneous pocket of the abdomen. The VNSdevice 300 may be powered and/or recharged from outside the body or mayhave its own power source 320. By way of example, the VNS device 300 maybe purchased commercially. The VNS device 300 is preferably programmedwith a physician programmer, such as a Model 7432 also available fromMedtronic, Inc.

The parameters of the modulation signal 400 are preferably programmable,such as the frequency, amplitude, duty cycle, pulse width, pulse shape,etc. In the case of an implanted pulse generator, programming may takeplace before or after implantation. For example, an implanted pulsegenerator may have an external device for communication of settings tothe generator. An external communication device may modify the pulsegenerator programming to improve treatment.

The electrical leads 350 and electrodes 340 are preferably selected toachieve respective impedances permitting a peak pulse voltage in therange from about 0.2 volts to about 20 volts.

The blocking and/or modulating impulse signal 410 preferably has afrequency, an amplitude, a duty cycle, a pulse width, a pulse shape,etc. selected to influence the therapeutic result, namely blockingand/or modulating some or all of the vagus nerve transmissions. Forexample the frequency may be about 1 Hz or greater, such as betweenabout 25 Hz to 3000 Hz, or between about 1000 Hz to about 2500 Hz.(These are notably higher frequencies than typical nerve stimulation ormodulation frequencies.) The modulation signal may have a pulse widthselected to influence the therapeutic result, such as about 20 μS orgreater, such as about 20 μS to about 1000 μS. The modulation signal mayhave a peak voltage amplitude selected to influence the therapeuticresult, such as about 0.2 volts or greater, such as about 0.2 volts toabout 20 volts.

In accordance with a preferred embodiment, VNS devices 300 in accordancewith the present invention are provided in the form of a percutaneous orsubcutaneous implant that can be reused by an individual.

In accordance with another embodiment, devices in accordance with thepresent invention are provided in a “pacemaker” type form, in whichelectrical impulses 410 are generated to a selected region 200A, 200B ofthe vagus nerve 200 by VNS device 300 on an intermittent basis to createin the patient a lower reactivity of the vagus nerve 200 to upregulationsignals.

In accordance with another embodiment, devices 300 in accordance withthe present invention are incorporated in an endotracheal tube device toameliorate bronchospasm during surgery. In a preferred embodiment one ormore devices 300 are located in the distal portion of an endotrachealtube to contact selected regions 200A, 200B of the vagus nerve 200 toimpart appropriate electrical impulses to dampen reactivity of the vagusnerve 200 to stimulus. In all cases of permanent implantation, however,the implanting surgeon should vary the signal modulated by the controlunit 330 and specific location of the lead 350 until the desired outcomeis achieved, and should monitor the long-term maintenance of this effectto ensure that adaptive mechanisms in the patient's body do not nullifythe intended effects.

In addition, or as an alternative to the devices to implement themodulation unit for producing the electrical voltage/current profile ofthe blocking and/or modulating impulse to the electrodes, the devicedisclosed in U.S. Patent Publication No.: 2005/0216062 (the entiredisclosure of which is incorporated herein by reference), may beemployed. U.S. Patent Publication No.: 2005/0216062 discloses amulti-functional electrical stimulation (ES) system adapted to yieldoutput signals for effecting faradic, electromagnetic or other forms ofelectrical stimulation for a broad spectrum of different biological andbiomedical applications. The system includes an ES signal stage having aselector coupled to a plurality of different signal generators, eachproducing a signal having a distinct shape such as a sine, a square or asaw-tooth wave, or simple or complex pulse, the parameters of which areadjustable in regard to amplitude, duration, repetition rate and othervariables. The signal from the selected generator in the ES stage is fedto at least one output stage where it is processed to produce a high orlow voltage or current output of a desired polarity whereby the outputstage is capable of yielding an electrical stimulation signalappropriate for its intended application. Also included in the system isa measuring stage which measures and displays the electrical stimulationsignal operating on the substance being treated as well as the outputsof various sensors which sense conditions prevailing in this substancewhereby the user of the system can manually adjust it or have itautomatically adjusted by feedback to provide an electrical stimulationsignal of whatever type he wishes and the user can then observe theeffect of this signal on a substance being treated.

Prior to discussing experimental results, a general approach to treatingbronchial constriction in accordance with one or more embodiments of theinvention may include a method of (or apparatus for) treating bronchialconstriction associated with anaphylactic shock or asthma, comprisingapplying at least one electrical impulse to one or more selected regionsof the vagus nerve of a mammal in need of relief of bronchialconstriction.

The method may include: implanting one or more electrodes to theselected regions of the vagus nerve; and applying one or more electricalstimulation signals to the electrodes to produce the at least oneelectrical impulse, wherein the one or more electrical stimulationsignals are of a frequency between about 1 Hz to 3000 Hz, and anamplitude of between about 1-6 volts.

The one or more electrical stimulation signals may be of a frequencybetween about 750 Hz to 1250 Hz; or between about 15 Hz to 35 Hz. Theone or more electrical stimulation signals may be of an amplitude ofbetween about 0.75 to 1.25 volts, preferably about 1.0 volts. The one ormore electrical stimulation signals may be one or more of a full orpartial sinusoid, square wave, rectangular wave, and/or triangle wave.The one or more electrical stimulation signals may have a pulsed on-timeof between about 50 to 500 microseconds, such as about 100, 200 or 400microseconds.

The polarity of the pulses may be maintained either positive ornegative. Alternatively, the polarity of the pulses may be positive forsome periods of the wave and negative for some other periods of thewave. By way of example, the polarity of the pulses may be altered aboutevery second.

While upregulating the signal provided by the sympathetic nerves mayaccomplish the desired treatment effect, the present invention suggeststhat a more direct route to immediately breaking the cycle ofbronchoconstriction or hypotension is via the vagus nerve because themode of action for the hypersensitivity response in bronchoconstrictionor hypotension is at the vagus nerve and not through the sympatheticnerves. Therefore, experiments were performed to identify exemplarymethods of how electrical signals can be supplied to the peripheralnerve fibers that innervate and/or control the bronchial smooth muscleto (i) reduce the sensitivity of the muscle to the signals to constrict,and (ii) to blunt the intensity of, or break the constriction once ithas been initiated.

In particular, specific signals, selected from within a range of knownnerve signals, were applied to the vagus nerves and/or the sympatheticnerves in guinea pigs, to produce selective interruption or reduction inthe effects of lung vagal nerve activity leading to attenuation ofhistamine-induced bronchoconstriction.

Male guinea pigs (400 g) were transported to the lab and immediatelyanesthetized with an i.p. injection of urethane 1.5 g/kg. Skin over theanterior neck was opened and the carotid artery and both jugular veinswere cannulated with PE50 tubing to allow for blood pressure/heart ratemonitoring and drug administration, respectively. The trachea wascannulated and the animal ventilated by positive pressure, constantvolume ventilation followed by paralysis with succinylcholine (10ug/kg/min) to paralyze the chest wall musculature to remove thecontribution of chest wall rigidity from airway pressure measurements.

Guanethidine (10 mg/kg i.v.) was given to deplete norepinephrine fromnerve terminals that may interfere with vagal nerve stimulation. Bothvagus nerves were exposed and connected to electrodes to allow selectivestimuli of these nerves. Following 15 minutes of stabilization, baselinehemodynamic and airway pressure measurements were made before and afterthe administration of repetitive doses of i.v. histamine.

Following the establishment of a consistent response to i.v. histamine,vagal nerve stimulation was attempted at variations of frequency,voltage and pulse duration to identity parameters that attenuateresponses to i.v. histamine. Bronchoconstriction in response to i.v.histamine is known to be due both to direct airway smooth muscle effectsand to stimulation of vagal nerves to release acetylcholine.

At the end of vagal nerve challenges, atropine was administered i.v.before a subsequent dose of histamine to determine what percentage ofthe histamine-induced bronchoconstriction was vagal nerve induced. Thiswas considered a 100% response. Success of electrical interruption invagal nerve activity in attenuating histamine-inducedbronchoconstriction was compared to this maximum effect. Euthanasia wasaccomplished with intravenous potassium chloride.

In order to measure the bronchoconstriction, the airway pressure wasmeasured in two places. The blood pressure and heart rate were measuredto track the subjects' vital signs. In all the following graphs, the topline BP shows blood pressure, second line AP1 shows airway pressure,third line AP2 shows airway pressure on another sensor, the last line HRis the heart rate derived from the pulses in the blood pressure.

In the first animals, the signal frequency applied was varied from lessthan 1 Hz through 2,000 Hz, and the voltage was varied from 1V to 12V.Initial indications seemed to show that an appropriate signal was 1,000Hz, 400 μs, and 6-10V.

FIG. 5 graphically illustrates exemplary experimental data on guinea pig#2. More specifically, the graphs of FIG. 5 show the effect of a 1000Hz, 400 μS, 6V square wave signal applied simultaneously to both leftand right branches of the vagus nerve in guinea pig #2 when injectedwith 12 μg/kg histamine to cause airway pressure to increase. The firstpeak in airway pressure is histamine with the electric signal applied tothe vagus, the next peak is histamine alone (signal off), the third peakis histamine and signal again, fourth peak is histamine alone again. Itis clearly shown that the increase in airway pressure due to histamineis reduced in the presence of the 1000 Hz, 400 μS, 6V square wave on thevagus nerve. The animal's condition remained stable, as seen by the factthat the blood pressure and heart rate are not affected by thiselectrical signal.

After several attempts on the same animal to continue to reproduce thiseffect with the 1,000 Hz signal, however, we observed that the abilityto continuously stimulate and suppress airway constriction wasdiminished, and then lost. It appeared that the nerve was no longerconducting. This conclusion was drawn from the facts that (i) there wassome discoloration of the nerve where the electrode had been makingcontact, and (ii) the effect could be resuscitated by moving the leaddistally to an undamaged area of the nerve, i.e. toward the organs, butnot proximally, i.e., toward the brain. The same thing occurred withanimal #3. It has been hypothesized that the effect seen was, therefore,accompanied by a damaging of the nerve, which would not be clinicallydesirable.

To resolve the issue, in the next animal (guinea pig #4), we fabricateda new set of electrodes with much wider contact area to the nerve. Withthis new electrode, we started investigating signals from 1 hz to 3,000Hz again. This time, the most robust effectiveness and reproducibilitywas found at a frequency of 25 Hz, 400 μs, 1V.

FIG. 6 graphically illustrates exemplary experimental data on guinea pig#5. The graphs of FIG. 6 show the effect of a 25 Hz, 400 μS, 1V squarewave signal applied to both left and right vagus nerve in guinea pig #5when injected with 8 μg/kg histamine to cause airway pressure toincrease. The first peak in airway pressure is from histamine alone, thenext peak is histamine and signal applied. It is clearly shown that theincrease in airway pressure due to histamine is reduced in the presenceof the 25 Hz, 400 μS, 1V square wave on the vagus nerve.

FIG. 7 graphically illustrates additional exemplary experimental data onguinea pig #5. The graphs of FIG. 7 show the effect of a 25 Hz, 200 μS,1V square wave signal applied to both of the left and right vagus nervesin guinea pig #5 when injected with 8 μg/kg histamine to cause airwaypressure to increase. The second peak in airway pressure is fromhistamine alone, the first peak is histamine and signal applied. It isclearly shown that the increase in airway pressure due to histamine isreduced in the presence of the 25 Hz, 200 μS, 1V square wave on thevagus nerve. It is clear that the airway pressure reduction is evenbetter with the 200 μS pulse width than the 400 μS signal.

FIG. 8 graphically illustrates further exemplary experimental data onguinea pig #5. The graphs of FIG. 8 show repeatability of the effectseen in the previous graph. The animal, histamine and signal are thesame as the graphs in FIG. 7.

It is significant that the effects shown above were repeated severaltimes with this animal (guinea pig #5), without any loss of nerveactivity observed. We could move the electrodes proximally and distallyalong the vagus nerve and achieve the same effect. It was, therefore,concluded that the effect was being achieved without damaging the nerve.

FIG. 9 graphically illustrates subsequent exemplary experimental data onguinea pig #5. The graphs of FIG. 9 show the effect of a 25 Hz, 100 μS,1V square wave that switches polarity from + to − voltage every second.This signal is applied to both left and right vagus nerve in guinea pig#5 when injected with 8 μg/kg histamine to cause airway pressure toincrease. From left to right, the vertical dotted lines coincide withairway pressure events associated with: (1) histamine alone (largeairway spike—followed by a very brief manual occlusion of the airwaytube); (2) histamine with a 200 μS signal applied (smaller airwayspike); (3) a 100 μS electrical signal alone (no airway spike); (4)histamine with a 100 uS signal applied (smaller airway spike again); (5)histamine alone (large airway spike); and (6) histamine with the 100 μSsignal applied.

This evidence strongly suggests that the increase in airway pressure dueto histamine can be significantly reduced by the application of a 25 Hz,100 μS, 1V square wave with alternating polarity on the vagus nerve.

FIG. 10 graphically illustrates exemplary experimental data on guineapig #6. The graphs in FIG. 10 show the effect of a 25 Hz, 200 μS, 1Vsquare wave that switches polarity from + to − voltage every second.This signal is applied to both left and right vagus nerve in guinea pig#6 when injected with 16 μg/kg histamine to cause airway pressure toincrease. (Note that this animal demonstrated a very high tolerance tothe effects of histamine, and therefore was not an ideal test subjectfor the airway constriction effects, however, the animal did provide uswith the opportunity to test modification of other signal parameters.)

In this case, the first peak in airway pressure is from histamine alone,the next peak is histamine with the signal applied. It is clearly shownthat the increase in airway pressure due to histamine is reducedmoderately in its peak, and most definitely in its duration, when in thepresence of the 25 Hz, 200 μS, 1V square wave with alternating polarityon the vagus nerve.

FIG. 11 graphically illustrates additional exemplary experimental dataon guinea pig #6. As mentioned above, guinea pig #6 in the graphs ofFIG. 10 above needed more histamine than other guinea pigs (16-20 μg/kgvs 8 μg/kg) to achieve the desired increase in airway pressure. Also,the beneficial effects of the 1V signal were less pronounced in pig #6than in #5. Consequently, we tried increasing the voltage to 1.5V. Thefirst airway peak is from histamine alone (followed by a series ofmanual occlusions of the airway tube), and the second peak is the resultof histamine with the 1.5V, 25 Hz, 200 μS alternating polarity signal.The beneficial effects are seen with slightly more impact, but notsubstantially better than the 1V.

FIG. 12 graphically illustrates further exemplary experimental data onguinea pig #6. Since guinea pig #6 was losing its airway reaction tohistamine, we tried to determine if the 25 Hz, 200 μS, 1V, alternatingpolarity signal could mitigate the effects of a 20V, 20 Hz airwaypressure stimulating signal that has produced a simulated asthmaticresponse. The first airway peak is the 20V, 20 Hz stimulator signalapplied to increase pressure, then switched over to the 25 Hz, 200 μS,1V, alternating polarity signal. The second peak is the 20V, 20 Hzsignal alone. The first peak looks modestly lower and narrower than thesecond. The 25 Hz, 200 μS, 1V signal may have some beneficial airwaypressure reduction after electrical stimulation of airway constriction.

FIG. 13 graphically illustrates subsequent exemplary experimental data.On guinea pig #6 we also investigated the effect of the 1V, 25 Hz, and200 μS alternating polarity signal. Even after application of the signalfor 10 minutes continuously, there was no loss of nerve conduction orsigns of damage.

FIG. 14 graphically illustrates exemplary experimental data on guineapig #8. The graph below shows the effect of a 25 Hz, 200 μS, 1V squarewave that switches polarity from + to − voltage every second. Thissignal is applied to both left and right vagus nerve in guinea pig #8when injected with 12 μg/kg histamine to cause airway pressure toincrease. The first peak in airway pressure is from histamine alone, thenext peak is histamine with the signal applied. It is clearly shown thatthe increase in airway pressure due to histamine is reduced in thepresence of the 25 Hz, 200 μS, 1V square wave with alternating polarityon the vagus nerve. We have reproduced this effect multiple times, on 4different guinea pigs, on 4 different days.

The airway constriction induced by histamine in guinea pigs can besignificantly reduced by applying appropriate electrical signals to thevagus nerve.

We found at least 2 separate frequency ranges that have this effect. At1000 Hz, 6V, 400 μS the constriction is reduced, but there is evidencethat this is too much power for the nerve to handle. This may bemitigated by different electrode lead design in future tests. Differenttypes of animals also may tolerate differently differing power levels.

With a 25 Hz, 1V, 100-200 μS signal applied to the vagus nerve, airwayconstriction due to histamine is significantly reduced. This has beenrepeated on multiple animals many times. There is no evidence of nervedamage, and the power requirement of the generator is reduced by afactor of between 480 (40×6×2) and 960 (40×6×4) versus the 1000 Hz, 6V,400 μS signal.

Application of the signal to the vagus nerve appears to have someeffects lasting long after the signal is removed. Specific, repeatableexperimentation may be done to substantiate these longer lastingeffects. Additional testing on the guinea pig model may quantify theextent to which longer lasting effects remain after stimulation isremoved.

Additional tests may determine also if the reduction in airway pressureis due primarily to one branch of the vagus nerve, i.e., the left branchor the right branch.

In U.S. patent application Ser. No. 10/990,938 filed Nov. 17, 2004(Publication Number US2005/0125044A1), Kevin J. Tracey proposes a methodof treating many diseases including, among others, asthma, anaphylacticshock, sepsis and septic shock by electrical stimulation of the vagusnerve. However, the examples in the Tracey application use an electricalsignal that is 1 to 5V, 1 Hz and 2 mS to treat endotoxic shock, and noexamples are shown that test the proposed method on an asthma model, ananaphylactic shock model, or a sepsis model. The applicants of thepresent application performed additional testing to determine ifTracey's proposed method has any beneficial effect on asthma or bloodpressure in the model that shows efficacy with the method used in thepresent application. The applicants of the present application sought todetermine whether Tracey's signals can be applied to the vagus nerve toattenuate histamine-induced bronchoconstriction and increase in bloodpressure in guinea pigs.

Male guinea pigs (400 g) were transported to the lab and immediatelyanesthetized with an i.p. injection of urethane 1.5 g/kg. Skin over theanterior neck was opened and the carotid artery and both jugular veinsare cannulated with PE50 tubing to allow for blood pressure/heart ratemonitoring and drug administration, respectively. The trachea wascannulated and the animal ventilated by positive pressure, constantvolume ventilation followed by paralysis with succinylcholine (10ug/kg/min) to paralyze the chest wall musculature to remove thecontribution of chest wall rigidity from airway pressure measurements.

Guanethidine (10 mg/kg i.v.) was given to deplete norepinephrine fromnerve terminals that may interfere with vagal nerve stimulation. Bothvagus nerves were exposed and connected to electrodes to allow selectivestimuli of these nerves. Following 15 minutes of stabilization, baselinehemodynamic and airway pressure measurements were made before and afterthe administration of repetitive doses of i.v. histamine.

Following the establishment of a consistent response to i.v. histamine,vagal nerve stimulation was attempted at variations of 1 to 5 volts, 1Hz, 2 mS to identity parameters that attenuate responses to i.v.histamine. Bronchoconstriction in response to i.v. histamine is known tobe due to both direct airway smooth muscle effects and due tostimulation of vagal nerves to release acetylcholine.

At the end of vagal nerve challenges atropine was administered i.v.before a subsequent dose of histamine to determine what percentage ofthe histamine-induced bronchoconstriction was vagal nerve induced. Thiswas considered a 100% response. Success of electrical interruption invagal nerve activity in attenuating histamine-inducedbronchoconstriction was compared to this maximum effect. Euthanasia wasaccomplished with intravenous potassium chloride.

In order to measure the bronchoconstriction, the airway pressure wasmeasured in two places. The blood pressure and heart rate were measuredto track the subjects' vital signs. In all the following graphs, the topline BP (red) shows blood pressure, second line AP1 shows airwaypressure, third line AP2 shows airway pressure on another sensor, thelast line HR is the heart rate derived from the pulses in the bloodpressure.

FIG. 15 graphically illustrates exemplary experimental data from a firstexperiment on another guinea pig. The graph shows the effects ofTracey's 1V, 1 Hz, 2 mS waveform applied to both vagus nerves on theguinea pig. The first peak in airway pressure is from histamine alone,after which Tracey's signal was applied for 10 minutes as proposed inTracey's patent application. As seen from the second airway peak, thesignal has no noticeable effect on airway pressure. The animal's vitalsigns actually stabilized, seen in the rise in blood pressure, after thesignal was turned off.

FIG. 16 graphically illustrates exemplary experimental data from asecond experiment on the guinea pig in FIG. 15. The graph shows theeffects of Tracey's 1V, 1 Hz, 2 mS waveform with the polarity reversed(Tracey did not specify polarity in the patent application) applied toboth vagus nerves on the guinea pig. Again, the signal has no beneficialeffect on airway pressure. In fact, the second airway peak from thesignal and histamine combination is actually higher than the first peakof histamine alone.

FIG. 17 graphically illustrates exemplary experimental data from a thirdexperiment on the guinea pig in FIG. 15. The graph shows the effects ofTracey's 1V, 1 Hz, 2 mS waveform applied to both vagus nerves on theguinea pig. Again, the signal has no beneficial effect on airwaypressure. Instead, it increases airway pressure slightly throughout theduration of the signal application.

FIG. 18 graphically illustrates additional exemplary experimental datafrom an experiment on a subsequent guinea pig. The graph shows, fromleft to right, application of the 1.2V, 25 Hz, 0.2 mS signal disclosedin the present application, resulting in a slight decrease in airwaypressure in the absence of additional histamine. The subsequent threeelectrical stimulation treatments are 1V, 5V, and 2.5V variations ofTracey's proposed signal, applied after the effects of a histamineapplication largely had subsided. It is clear that the Tracey signals donot cause a decrease in airway pressure, but rather a slight increase,which remained and progressed over time.

FIG. 19 graphically illustrates further exemplary experimental data fromadditional experiments using signals within the range of Tracey'sproposed examples. None of the signals proposed by Tracey had anybeneficial effect on airway pressure. Factoring in a potential range ofsignals, one experiment used 0.75V, which is below Tracey's proposedrange, but there was still no beneficial effect on airway pressure.

FIG. 20 graphically illustrates exemplary experimental data fromsubsequent experiments showing the effect of Tracey's 5V, 1 Hz, 2 mSsignal, first without and then with additional histamine. It is clearthat the airway pressure increase is even greater with the signal, asthe airway pressure progressively increased during the course of signalapplication. Adding the histamine after prolonged application of theTracey signal resulted in an even greater increase in airway pressure.

The full range of the signal proposed by Tracey in his patentapplication was tested in the animal model of the present application.No reduction in airway pressure was seen. Most of the voltages resultedin detrimental increases in airway pressure and detrimental effects tovital signs, such as decreases in blood pressure.

Treatment Approach 2

With reference to the drawings wherein like numerals indicate likeelements there are shown in FIGS. 21 and 22 schematic diagrams of thehuman autonomic nervous system, including sympathetic fibers,parasympathetic fibers, and cerebral nerves.

The sympathetic nerve fibers, along with many of the spinal cord's nerveroot fibers, and the cranial nerves that innervate tissue in thethoracic and abdominal cavities are sometimes referred to as theautonomic, or vegetative, nervous system. The sympathetic, spinal, andcranial nerves all have couplings to the central nervous system,generally in the primitive regions of the brain, however, thesecomponents have direct effects over many regions of the brain, includingthe frontal cortex, thalamus, hypothalamus, hippocampus, and cerebellum.The central components of the spinal cord and the sympathetic nervechain extend into the periphery of the autonomic nervous system fromtheir cranial base to the coccyx, essentially passing down the entirespinal column, including the cervical, thoracic and lumbar regions. Thesympathetic chain extends on the anterior of the column, while thespinal cord components pass through the spinal canal. The cranialnerves, the one most innervating of the rest of the body being the vagusnerve, passes through the dura mater into the neck, and then along thecarotid and into the thoracic and abdominal cavities, generallyfollowing structures like the esophagus, the aorta, and the stomachwall.

Because the autonomic nervous system has both afferent and efferentcomponents, modulation of its fibers can affect both the end organs(efferent) as well as the brain structure to which the afferents fibersare ultimately coupled within the brain.

Although sympathetic and cranial fibers (axons) transmit impulsesproducing a wide variety of differing effects, their component neuronsare morphologically similar. They are smallish, ovoid, multipolar cellswith myelinated axons and a variable number of dendrites. All the fibersform synapses in peripheral ganglia, and the unmyelinated axons of theganglionic neurons convey impulses to the viscera, vessels and otherstructures innervated. Because of this arrangement, the axons of theautonomic nerve cells in the nuclei of the cranial nerves, in thethoracolumbar lateral comual cells, and in the gray matter of the sacralspinal segments are termed preganglionic sympathetic nerve fibers, whilethose of the ganglion cells are termed postganglionic sympathetic nervefibers. These postganglionic sympathetic nerve fibers converge, in smallnodes of nerve cells, called ganglia that lie alongside the vertebralbodies in the neck, chest, and abdomen. The effects of the ganglia aspart of the autonomic system are extensive. Their effects range from thecontrol of insulin production, cholesterol production, bile production,satiety, other digestive functions, blood pressure, vascular tone, heartrate, sweat, body heat, blood glucose levels, and sexual arousal.

The parasympathetic group lies predominately in the cranial and cervicalregion, while the sympathetic group lies predominantly in the lowercervical, and thoracolumbar and sacral regions. The sympatheticperipheral nervous system is comprised of the sympathetic ganglia thatare ovoid/bulb like structures (bulbs) and the paravertebral sympatheticchain (cord that connects the bulbs). The sympathetic ganglia includethe central ganglia and the collateral ganglia.

The central ganglia are located in the cervical portion, the thoracicportion, the lumbar portion, and the sacral portion. The cervicalportion of the sympathetic system includes the superior cervicalganglion, the middle cervical ganglion, and the interior cervicalganglion.

The thoracic portion of the sympathetic system includes twelve ganglia,five upper ganglia and seven lower ganglia. The seven lower gangliadistribute filaments to the aorta, and unite to form the greater, thelesser, and the lowest splanchnic nerves. The greater splanchnic nerve(splanchnicus major) is formed by branches from the fifth to the ninthor tenth thoracic ganglia, but the fibers in the higher roots may betraced upward in the sympathetic trunk as far as the first or secondthoracic ganglion. The greater splanchnic nerve descends on the bodiesof the vertebrae, perforates the crus of the diaphragm, and ends in theceliac ganglion of the celiac plexus. The lesser splanchnic nerve(splanchnicus minor) is formed by filaments from the ninth and tenth,and sometimes the eleventh thoracic ganglia, and from the cord betweenthem. The lesser splanchnic nerve pierces the diaphragm with thepreceding nerve, and joins the aorticorenal ganglion. The lowestsplanchnic nerve (splanchnicus imus) arises from the last thoracicganglion, and, piercing the diaphragm, ends in the renal plexus.

The lumbar portion of the sympathetic system usually includes fourlumbar ganglia, connected together by interganglionic cords. The lumbarportion is continuous above, with the thoracic portion beneath themedial lumbocostal arch, and below with the pelvic portion behind thecommon iliac artery. Gray rami communicantes pass from all the gangliato the lumbar spinal nerves. The first and second, and sometimes thethird, lumbar nerves send white rami communicantes to the correspondingganglia.

The sacral portion of the sympathetic system is situated in front of thesacrum, medial to the anterior sacral foramina. The sacral portionincludes four or five small sacral ganglia, connected together byinterganglionic cords, and continuous above with the abdominal portion.Below, the two pelvic sympathetic trunks converge, and end on the frontof the coccyx in a small ganglion.

The collateral ganglia include the three great gangliated plexuses,called, the cardiac, the celiac (solar or epigastric), and thehypogastric plexuses. The great plexuses are respectively situated infront of the vertebral column in the thoracic, abdominal, and pelvicregions. They consist of collections of nerves and ganglia; the nervesbeing derived from the sympathetic trunks and from the cerebrospinalnerves. They distribute branches to the viscera.

Although all of the great plexuses (and their sub-parts) are of interestin accordance with various embodiments of the present invention, by wayof example, the celiac plexus is shown in FIGS. 21 and 22 in moredetail. The celiac plexus is the largest of the three great sympatheticplexuses and is located at the upper part of the first lumbar vertebra.The celiac plexus is composed of the celiac ganglia and a network ofnerve fibers uniting them together. The celiac plexus and the gangliareceive the greater and lesser splanchnic nerves of both sides and somefilaments from the right vagus nerve. The celiac plexus gives offnumerous secondary plexuses along the neighboring arteries. The upperpart of each celiac ganglion is joined by the greater splanchnic nerve,while the lower part, which is segmented off and named the aorticorenalganglion, receives the lesser splanchnic nerve and gives off the greaterpart of the renal plexus.

The secondary plexuses associated with the celiac plexus consist of thephrenic, hepatic, lineal, superior gastric, suprarenal, renal,spermatic, superior mesenteric, abdominal aortic, and inferiormesenteric. The phrenic plexus emanates from the upper part of theceliac ganglion and accompanies the inferior phrenic artery to thediaphragm, with some filaments passing to the suprarenal gland andbranches going to the inferior vena cava, and the suprarenal and hepaticplexuses. The hepatic plexus emanates from the celiac plexus andreceives filaments from the left vagus and right phrenic nerves. Thehepatic plexus accompanies the hepatic artery and ramifies upon itsbranches those of the portal vein in the substance of the liver.Branches from hepatic plexus accompany the hepatic artery, thegastroduodenal artery, and the right gastroepiploic artery along thegreater curvature of the stomach.

The lienal plexus is formed from the celiac plexus, the left celiacganglion, and from the right vagus nerve. The lienal plexus accompaniesthe lienal artery to the spleen, giving off subsidiary plexuses alongthe various branches of the artery. The superior gastric plexusaccompanies the left gastric artery along the lesser curvature of thestomach, and joins with branches from the left vagus nerve. Thesuprarenal plexus is formed from the celiac plexus, from the celiacganglion, and from the phrenic and greater splanchnic nerves. Thesuprarenal plexus supplies the suprarenal gland. The renal plexus isformed from the celiac plexus, the aorticorenal ganglion, and the aorticplexus, and is joined by the smallest splanchnic nerve. The nerves fromthe suprarenal plexus accompany the branches of the renal artery intothe kidney, the spermatic plexus, and the inferior vena cava.

The spermatic plexus is formed from the renal plexus and aortic plexus.The spermatic plexus accompanies the internal spermatic artery to thetestis (in the male) and the ovarian plexus, the ovary, and the uterus(in the female). The superior mesenteric plexus is formed from the lowerpart of the celiac plexus and receives branches from the right vagusnerve.

The superior mesenteric plexus surrounds the superior mesenteric arteryand accompanies it into the mesentery, the pancreas, the smallintestine, and the great intestine. The abdominal aortic plexus isformed from the celiac plexus and ganglia, and the lumbar ganglia. Theabdominal aortic plexus is situated upon the sides and front of theaorta, between the origins of the superior and inferior mesentericarteries, and distributes filaments to the inferior vena cava. Theinferior mesenteric plexus is formed from the aortic plexus. Theinferior mesenteric plexus surrounds the inferior mesenteric artery, thedescending and sigmoid parts of the colon and the rectum.

While the sympathetic and parasympathetic nervous system extends betweenthe brain and the great plexuses, the cranial nerves extend between thebrain and the great plexuses along other paths. For example, as bestseen in FIG. 22, the sympathetic and parasympathetic nerves extendbetween the brain the celiac plexus along a first portion of a“circuit,” while the vagus nerve extends between the brain the celiacplexus along a second portion of the same circuit.

There are twelve pairs of cranial nerves, namely: the olfactory, optic,oculomotor, trochlear, trigeminal, abducent, facial, acoustic,glossopharyngeal, vagus, accessory, and hypoglossal. The nuclei oforigin of the motor nerves and the nuclei of termination of the sensorynerves are brought into relationship with the cerebral cortex.

Although all of the cranial nerves are of interest in accordance withvarious embodiments of the present invention, by way of example, thevagus nerve is shown in FIGS. 21 and 22 in more detail. The vagus nerveis composed of motor and sensory fibers and is of considerable interestin connection with various embodiments of the present invention becauseit has a relatively extensive distribution than the other cranial nervesand passes through the neck and thorax to the abdomen. The vagus nervesleaves the cranium and is contained in the same sheath of dura materwith the accessory nerve. The vagus nerve passes down the neck withinthe carotid sheath to the root of the neck. On the right side, the nervedescends by the trachea to the back of the root of the lung, where itspreads out in the posterior pulmonary plexus. From the posteriorpulmonary plexus, two cords descend on the esophagus and divide to formthe esophageal plexus. The branches combine into a single cord, whichruns along the back of the esophagus, enters the abdomen, and isdistributed to the posteroinferior surface of the stomach, joining theleft side of the celiac plexus, and sending filaments to the lienalplexus.

On the left side, the vagus nerve enters the thorax, crosses the leftside of the arch of the aorta, and descends behind the root of the leftlung, forming the posterior pulmonary plexus. From posterior pulmonaryplexus, the vagus nerve extends along the esophagus, to the esophagealplexus, and then to the stomach. The vagus nerve branches over theanterosuperior surface of the stomach, the fundus, and the lessercurvature of the stomach.

The branches of distribution of the vagus nerve are as follows: theauricular, the superior laryngeal, the recurrent, the superior cardiac,the inferior cardiac, the anterior bronchial, the posterior bronchial,the esophageal, the celiac, and the hepatic. Although all of thebranches of the vagus nerve are of interest in accordance with variousembodiments of the invention, the gastric branches and the celiacbranches are believed to be of notable interest. The gastric branchesare distributed to the stomach, where the right vagus nerve forms theposterior gastric plexus on the posteroinferior surface of the stomachand the left vagus nerve forms the anterior gastric plexus on theantero-superior surface of the stomach. The celiac branches are mainlyderived from the right vagus nerve, which enter the celiac plexus andsupply branches to the pancreas, spleen, kidneys, suprarenal bodies, andintestine.

One or more embodiments of the present invention provide for one or moremethods of treating physiological disorders by at least one ofmonitoring and modulating one or more nerves and/or one or more muscleson both sides of a particular plexus. Although the various embodimentsof the invention are not limited by any particular theory of operation,it is believed that advantages are obtained when the disorder isassociated with organs and/or musculature enervated by the nervesentering or leaving the given plexus. For example, it is believed thatdisorders associated with bronchial restriction (e.g. asthma,anaphylaxis, etc.) may be better treated through electronic monitoringand/or electro-modulation of the nerves and/or musculature on both sidesof the cervical ganglion (and/or the esophageal plexus). In particular,it is believed that electrical (or chemical) modulation of: (i) one ormore of the sympathetic or parasympathetic nerves (discussed above) onthe one side of the appropriate plexus; and (ii) one or more of thevagus nerves (also discussed above) on the other side of the appropriateplexus, will improve the therapeutic effect on one or more pathologies.

Further reference is now made to FIG. 23, which illustrates a processflow of steps or actions, one or more of which may be carried out inaccordance with one or more embodiments of the present invention. Ataction 550, one or more electrodes 500 are implanted on or near at leastone of the sympathetic or parasympathetic nerves on one side of a targetplexus, such as the celiac plexus. On or more further electrodes 500 areimplanted on or near at least one of the cranial nerves entering orleaving the target plexus, or on or near at least one of the musclesenervated by such nerves. The electrodes 500 may be configured asmonopolar electrodes, with one electrode 500 per lead, or as multipolarelectrodes, with more than one electrode 500 per lead. Preferably, theelectrodes 500 are made from a biocompatible conductive material such asplatinum-iridium. Any of the known electrodes and leads may be used forthis purpose (such as from Medtronic, Model 4300). The electrodes 500are attached to the electrical leads prior to implantation and navigatedto a point near the desired modulation site. The electrical leads andelectrodes 500 may be surgically inserted into the patient using asurgical technique, such as laparotomy or laparoscopy, with proximalends of the leads located near the modulation unit 502 and distal endslocated near the desired modulation site.

At action 550 simultaneous monitoring of the nerve and/or muscleactivity on both sides of the target plexus is performed using themonitor circuit 502. Any of the known equipment operable to receiveelectrical signaling from the electrodes 500 and to produce graphicand/or tabular data therefrom may be employed. It is desirable that themonitor circuit 502 and/or a computer associated therewith is capable ofcorrelating and/or analyzing the received data to identify abnormalitiesin the activity of the nerves and/or muscles (action 554) or to identifya desired activity of the nerves and/or muscles (action 556) to achievethe therapeutic effect. For example, if a bronchial disorder (e.g.,asthma) were to be treated, the measured activity of the nerves and/ormuscles of the patient may indicate an abnormal bronchial restrictionprofile. If so, a desired profile may be formulated, which if achievedthrough modulation of the nerves and/or muscles would result in areduced desire to eat on the part of the patient.

At action 558, the modulation unit 502 is preferably programmed tomodulate the nerves and/or muscles on one or both sides of the targetplexus to achieve the therapeutic result (action 560). The modulationmay be achieved through electrical and/or chemical intervention. In thecase of electrical modulation, the preferred effect may be to stimulateor reversibly block nervous and or muscular tissue. Use of the termblock means disruption, modulation, and/or inhibition of nerve impulsetransmission and/or muscular flexion and inhibition. Abnormal regulationcan result in an excitation of the pathways or a loss of inhibition ofthe pathways, with the net result being an increased perception orresponse. Therapeutic measures can be directed towards either blockingthe transmission of signals or stimulating inhibitory feedback.Electrical stimulation permits such stimulation of the target neuralstructures and, equally importantly, prevents the total destruction ofthe nervous system. Additionally, electrical stimulation parameters canbe adjusted so that benefits are maximized and side effects areminimized.

The electrical voltage/current profile of the modulation signal to theelectrodes 500 (and thus the nerves/muscles) may be achieved using apulse generator (such as that discussed above with respect to FIG. 4).In a preferred embodiment, the modulation unit 502 includes a powersource, a processor, a clock, a memory, etc. to produce a pulse train tothe electrodes 500. The parameters of the modulation signal arepreferably programmable (action 558), such as the frequency, amplitude,duty cycle, pulse width, pulse shape, etc. The modulation unit 502 maybe surgically implanted, such as in a subcutaneous pocket of the abdomenor positioned outside the patient. By way of example, the modulationunit 502 may be purchased commercially, such as the Itrel 3 Model 7425available from Medtronic, Inc. The modulation unit 502 is preferablyprogrammed with a physician programmer, such as a Model 7432 alsoavailable from Medtronic, Inc.

The electrical leads and electrodes 500 are preferably selected toachieve respective impedances permitting a peak pulse current in therange from about 0.01 mA to about 100.0 mA.

The modulation signal may have a frequency selected to influence thetherapeutic result, such as from about 0.2 pulses per minute to about18,000 pulses per minute, depending on the application. The modulationsignal may have a pulse width selected to influence the therapeuticresult, such as from about 0.01 ms to 500.0 ms. The modulation signalmay have a peak current amplitude selected to influence the therapeuticresult, such as from about 0.01 mA to 100.0 mA.

In addition, or as an alternative to, the devices to implement themodulation unit 502 for producing the electrical voltage/current profileof the modulation signal to the electrodes 500, the device disclosed inU.S. Patent Publication No.: 2005/0216062, may be employed, which wasdiscussed in detail above.

As discussed above, the therapeutic treatment may also additionally oralternatively include using a pharmaceutical drug or drugs to modulatethe nerves and/or muscles. This may be accomplished by means of animplantable pump and a catheter to administer the drug(s). The catheterpreferably includes a discharge portion that lies adjacent apredetermined infusion site, e.g., one or more of the sites discussedabove (or below) in the treatment. The modulation unit 502 is preferablyoperable to communicate with the pump to administer the drug(s) atpredetermined dosage(s) in order to treat the disorder.

Treatment Approach 3

In accordance with one or more further embodiments of the presentinvention, a method of treating bronchial constriction includes inducingan electric field and/or electromagnetic field in the lungs of a mammalto reduce the over-growth of mucus, fibers, clogging, etc. of the lungs.For example, the electric field and/or electromagnetic field may beinduced to down-regulate one or more mitogenic factors, such as vascularendothelial growth factor (VEGF), and/or one or more enzymes, such asmatrix metalloproteinases (MMPs).

In the context of down-regulating VEGF, it is has been discovered thatwhen VEGF is expressed in the lungs of genetically engineered transgenicmice, asthma-like alterations develop. Indeed, the presence (and overexpression) of VEGF in mice produced many features of asthma, such asmucous formation, airway fibrosis and asthma-like pulmonary functionabnormalities. It has also been previously discovered that if VEGF isblocked, the asthma-like manifestations in mouse asthma models islikewise blocked.

VEGF is a mitogenic factor that stimulates angiogenesis. Angiogenesis isthe process of blood vessel growth (new capillary blood vessels asoutgrowths of pre-existing vessels) towards a tissue in need of oxygenor an injured tissue. Angiogenesis can be either harmful or beneficial,for example, in cases such as tumor growth, angiogenesis towards thetumor can supply the tumor with nutrients and support its growth, thusfurther harming the patient.

At the onset of angiogenesis, the quiescent endothelium is destabilizedinto migratory, proliferative endothelial cells. The angiogenic(activated) endothelium is maintained primarily by positive regulatorymolecules. In the absence of such molecules, the endothelium remains ina differentiated, quiescent state that is maintained by negativeregulatory molecules, angiogenesis inhibitors. Normally, the negativeand positive activities are balanced to maintain the vascularendothelium in quiescence. A shift in the balance of the positive andnegative regulatory molecules can alter the differentiated state of theendothelium from the non-angiogenic, quiescent to the angiogenic state.In the switch to pro-angiogenesis, the quiescent endothelial cells arestimulated to migrate toward a chemotactic stimulus, lining up in a tube(sprout) formation. These cells also secrete proteolytic enzymes thatdegrade the endothelial basement membrane, thus allowing the migratingendothelial cells to extend into the perivascular stroma to begin a newcapillary sprout. The angiogenic process is characterized by increasedproliferation of endothelial cells to form the extending capillary.

In accordance with one or more aspects of the present invention, themitogenic nature of the VEGF factor is believed to be the cause of thebronchial constrictions associated with, for example, asthma, and theresultant over-growth of mucus, fibers, clogging, etc. of the lungs.Thus, down-regulating the VEGF factor in treating the pathology isdesirable.

There are naturally occurring molecules that serve as negativeregulators of angiogenesis, such as angiostatin, a 38-45 kDa cleavageproduct of plasminogen, containing kringle domains 1-4 (K1-4). Variousattempts to block VEGF activity using non-natural means have also beenproposed. Inhibitory anti-VEGF receptor antibodies, soluble receptorconstructs, antisense strategies, RNA aptamers against VEGF and lowmolecular weight VEGF receptor tyrosine kinase (RTK) inhibitors have allbeen proposed for use in interfering with VEGF signaling. Monoclonalantibodies against VEGF have been shown to inhibit human tumor xenograftgrowth and ascites formation in mice. U.S. Pat. No. 6,342,221 to Thorpe,et al. discloses the use of anti-VEGF antibodies to specifically inhibitVEGF binding to the VEGFR-2 receptor.

The induction of electric field and/or electromagnetic field in thelungs to down-regulate VEGF, however, is an entirely different approachto treating bronchial constrictions (e.g., asthma). In accordance withone or more embodiments of the invention, the electric field and/orelectromagnetic field may be induced by way of externally disposedapparatus, such as a control unit (including a drive signal generator)and percutaneous field emitters, such as capacitive coupling electrodesand/or inductive coils. (Alternative embodiments of the presentinvention may provide for subcutaneous components, including the controlunit, signal generator, and/or the electrodes/coils).

The field emitters (whether disposed percutaneously or subcutaneously)are preferably located to direct the electric and/or electromagneticfields toward the lungs of the patient. By way of example, the fieldemitters may be disposed on the chest of the patient and/or on the backof the patient. Particular locations for the field emitters areconsidered well within the knowledge and/or skill of artisans in thefield.

The fields are induced by applying at least one electrical impulse thefield emitters, such as by using the signal generator to apply the drivesignals to the field emitters. By way of example, the drive signals mayinclude at least one of sine waves, square waves, triangle waves,exponential waves, and complex impulses. In one or more embodiments, thesignal generator may be implemented using a power source, a processor, aclock, a memory, etc. to produce the aforementioned waveforms, such as apulse train. The parameters of the drive signal are preferablyprogrammable, such as the frequency, amplitude, duty cycle, pulse width,pulse shape, etc. In the case of an implanted signal generator,programming may take place before or after implantation. For example, animplanted signal generator may have an external device for communicationof settings to the generator. An external communication device maymodify the signal generator programming to improve treatment.

By way of example, the parameters of the drive signal may include a sinewave profile having a frequency of between about 10 Hz to 100 KHz, aduty cycle of between about 1 to 100%, and an amplitude of between about1 mv/cm to about 50 mv/cm. The electric fields and/or electromagneticfields may be applied for a predetermined period of time, such asbetween about 0.5 to about 24 hours. The protocol of one or moreembodiments of the present invention may include measuring a response ofthe patient to the applied field(s). For example, the airway pressureand/or lung volume of the patient may be monitored and the parameters ofthe drive signal (and thus the induced fields) may be adjusted toimprove the treatment.

Studies have shown that people with allergies and asthma have an excessof T-helper type 2 cells (TH2); indeed, when VEGF is produced, the TH2response is increased. (This condition has been mimicked in mice by overexpressing VEGF in their lungs.) Thus, in accordance with one or moreaspects of the present invention, the aforementioned application ofelectric fields and/or electromagnetic fields in the patient's lungs maybe directed to the reduction of TH2 cells.

In one or more alternative embodiments, the application of electricfields and/or electromagnetic fields in the patient's lungs may bedirected to the down-regulation of one or more enzymes, such as one ormore matrix metalloproteinases (MMPs). MMPs are naturally-occurringenzymes found in most mammals. Over-expression and activation of MMPs oran imbalance between MMPs and inhibitors of MMPs have been suggested asfactors in the pathogenesis of diseases characterized by the breakdownof extracellular matrix or connective tissues. MMPs include one or moreof: Stromelysin-1, gelatinase A, fibroblast collagenase (MMP-1),neutrophil collagenase (MMP-8), gelatinase B (MMP-9), stromelysin-2(MMP-10), stromelysin-3 (MMP-11), matrilysin (MMP-7), collagenase 3(MMP-13), and TNF-alpha converting enzyme (TACE).

The MMP enzymes have been implicated with a number of diseases whichresult from breakdown of connective tissue, including such diseases asrheumatoid arthritis, osteoarthritis, osteoporosis, periodontitis,multiple sclerosis, gingivitis, corneal epidermal and gastriculceration, atherosclerosis, neointimal proliferation which leads torestenosis and ischemic heart failure, and tumor metastasis. A majorlimitation on the use of currently known MMP inhibitors is their lack ofspecificity for any particular enzyme. Recent data has established thatspecific MMP enzymes are associated with some diseases, with no effecton others. The MMPs are generally categorized based on their substratespecificity, and indeed the collagenase subfamily of MMP-1, MMP-8, andMMP-13 selectively cleave native interstitial collagens, and thus areassociated only with diseases linked to such interstitial collagentissue. This is evidenced by the recent discovery that MMP-13 alone isover expressed in breast carcinoma, while MMP-1 alone is over expressedin papillary carcinoma.

In accordance with one or more aspects of the present invention,however, the prevention and treatment of the aforementioned diseasesassociated with over-expression of MMPs (e.g., asthma) may be effectedby inhibiting metalloproteinase enzymes using application of electricfields and/or electromagnetic fields in the patient's lungs. This, inturn is believed to curtail and/or eliminate the breakdown of connectivetissues that results in the disease states.

Among the available devices to implement the control unit and/or signalgenerator for facilitating the emission of electric fields and/orelectromagnetic fields is a physician programmer, such as a Model 7432also available from Medtronic, Inc. An alternative control unit, signalgenerator is disclosed in U.S. Patent Publication No.: 2005/0216062, theentire disclosure of which is incorporated herein by reference. U.S.Patent Publication No.: 2005/0216062 discloses a multi-functionalelectrical stimulation (ES) system adapted to yield output signals foreffecting faradic, electromagnetic or other forms of electricalstimulation for a broad spectrum of different biological and biomedicalapplications. The system includes an ES signal stage having a selectorcoupled to a plurality of different signal generators, each producing asignal having a distinct shape such as a sine, a square or saw-toothwave, or simple or complex pulse, the parameters of which are adjustablein regard to amplitude, duration, repetition rate and other variables.The signal from the selected generator in the ES stage is fed to atleast one output stage where it is processed to produce a high or lowvoltage or current output of a desired polarity whereby the output stageis capable of yielding an electrical stimulation signal appropriate forits intended application. Also included in the system is a measuringstage which measures and displays the electrical stimulation signaloperating on the substance being treated as well as the outputs ofvarious sensors which sense conditions prevailing in this substancewhereby the user of the system can manually adjust it or have itautomatically adjusted by feedback to provide an electrical stimulationsignal of whatever type he wishes and the user can then observe theeffect of this signal on a substance being treated.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It is therefore to be understood that numerousmodifications may be made to the illustrative embodiments and that otherarrangements may be devised without departing from the spirit and scopeof the present invention as defined by the appended claims.

1. A method of treating bronchoconstriction comprising applying at leastone electrical impulse to a selected region of a parasympathetic nervoussystem of a patient, wherein the electrical impulse is sufficient toreduce a magnitude of constriction of bronchial smooth muscle in thepatient and wherein the electrical impulse has a frequency of about 10Hz to 50 Hz.
 2. The method set forth in claim 1 wherein the bronchialconstriction is associated with asthma or anaphylaxis.
 3. The method setforth in claim 1 wherein the selected region comprises a region of avagus nerve of the patient.
 4. The method of claim 1 further comprising:implanting one or more electrodes to the one or more selected regions ofthe parasympathetic nervous system of the patient; and applying one ormore electrical stimulation signals to the one or more electrodes toproduce the at least one electrical impulse,
 5. The method of claim 1wherein the electrical impulse has an amplitude of between about 1 to 12volts.
 6. The method of claim 1 wherein the electrical impulse is one ormore of a full or partial sinusoid, square wave, rectangular wave,triangle wave.
 7. The method of claim 1 wherein the electrical impulsehas a pulsed on-time of between about 50 to 500 microseconds.
 8. Themethod of claim 1 wherein the electrical impulse has a frequency ofbetween 15 Hz and 35 Hz inclusive.
 9. A method of treating asthma in apatient comprising applying at least one electrical impulse of 15 Hz to35 Hz inclusive to a selected region of a parasympathetic nervous systemof a patient.
 10. The method of claim 9 wherein the electrical impulseis sufficient to reduce a magnitude of constriction of bronchial smoothmuscle in the patient.
 11. The method set forth in claim 9 wherein theselected region comprises a region of a vagus nerve of the patient. 12.The method of claim 9 further comprising: implanting one or moreelectrodes to the one or more selected regions of the parasympatheticnervous system of the patient; and applying one or more electricalstimulation signals to the one or more electrodes to produce the atleast one electrical impulse,
 13. The method of claim 9 wherein theelectrical impulse has an amplitude of between about 1 to 12 volts. 14.The method of claim 9 wherein the electrical impulse is one or more of afull or partial sinusoid, square wave, rectangular wave, triangle wave.15. The method of claim 9 wherein the electrical impulse has a pulsedon-time of between about 50 to 500 microseconds.
 16. The method of claim9 wherein the electrical impulse has a frequency of between 15 Hz and 35Hz inclusive.